What are the tenets of clonal selection theory?
Each lymphocyte has a unique receptor, receptors are made before infection, antigen selects the matching cell, the cell proliferates, clones become effector and memory cells, and self-reactive cells are eliminated
Why is clonal selection theory relevant?
Explains specificity, immune memory, and how vaccines work
What is the difference between stem cells and stromal cells?
Stem cells become immune cells, stromal cells support development
How do stromal cells support development?
Through physical contact and soluble factors (cytokines)
What are examples of stromal support?
SCF–Kit (contact) and IL-7 (cytokine)
What happens in the Pro-B cell stage?
Heavy chain rearrangement
What happens in the Pre-B cell stage?
Heavy chain made, pre-BCR forms, proliferation
What happens in the immature B cell stage?
Light chain rearrangement and IgM expression
What happens in the mature naïve B cell stage?
IgM and IgD expression, leaves bone marrow
What is a pre-B cell receptor?
A test receptor for the heavy chain
What is the purpose of the surrogate light chain?
Tests if the heavy chain works
What are the surrogate light chains?
VpreB and λ5
How is the heavy chain tested?
Forms pre-BCR with surrogate light chain and must signal
What is a productive rearrangement?
Functional receptor with correct reading frame and no stop codon
What is a non-productive rearrangement?
Nonfunctional receptor due to frameshift or stop codon
What determines if rearrangement is productive?
In-frame sequence, no stop codon, full protein
What is the relationship between rearrangement and allelic exclusion?
Productive rearrangement stops the other allele; non-productive leads to trying the second allele
What is the difference between heavy and light chain rearrangement?
Heavy chain has one chance; light chain can retry and edit
What are the checkpoints of B cell development?
Heavy chain checkpoint, light chain checkpoint, self-tolerance checkpoint
What proteins are expressed early in B cell development?
CD19 and IL-7 receptor
What proteins are expressed mid-development?
Pre-BCR
What proteins are expressed later?
IgM and IgD
How does the heavy chain variable region attach to the constant region?
By RNA splicing
What is recombination vs splicing?
Recombination is DNA-level VDJ joining; splicing is RNA-level joining to constant region
Why is the order of constant regions important?
Determines antibody class
What is the role of alternative splicing?
Allows IgM and IgD expression
What happens during negative selection of B cells?
Self-reactive cells undergo apoptosis, anergy, or receptor editing
What is apoptosis?
Programmed cell death
What is anergy?
Cell becomes inactive
What is receptor editing?
Light chain is changed to avoid self-reactivity
Why can receptor editing only occur in light chains?
Heavy chain rearrangement is complete and cannot be redone
What is central tolerance?
Removal of self-reactive cells in bone marrow
What is peripheral tolerance?
Control of self-reactive cells outside bone marrow
Why is peripheral tolerance needed?
Not all self-antigens are in bone marrow
What are B1 and marginal zone B cells?
Innate-like, fast responders
What are B2 cells?
Conventional adaptive B cells
Where does T cell development begin and end?
Begins in bone marrow, ends in thymus
What is a thymocyte?
Developing T cell
What is the difference between cells entering and leaving thymus?
Entering are immature; leaving are CD4 or CD8 mature cells
What is the role of the Notch receptor?
Drives T cell development
What happens to the thymus over time?
Shrinks after puberty (involution)
What are the regions of the thymus?
Cortex and medulla
What happens in the cortex?
Positive selection
What happens in the medulla?
Negative selection
What are the stages of T cell development?
DN → DP → SP
How long does T cell development take?
About 2–3 weeks
What does the CD4
CD8 flow plot show? / None → both → one
What does the CD44
CD25 flow plot show? / 44 → both → 25 → none
What are double negative cells?
No CD4 or CD8
What are double positive cells?
Both CD4 and CD8
What are DN1 cells?
Earliest stage, entry into thymus
What happens in DN2 cells?
TCR rearrangement begins
What happens in DN3 cells?
β chain rearrangement and pre-TCR checkpoint
What happens in DN4 cells?
Proliferation and CD4/CD8 expression
What are αβ T cells?
Most common, adaptive
What are γδ T cells?
Less common, innate-like
What is the pre-TCR made of?
β chain + pTα + CD3
What is β-selection?
Checkpoint testing β chain function
What is positive selection?
Keeps T cells that recognize self-MHC
What is self-restriction?
T cells must recognize antigen with self-MHC
What is the goldilocks model?
Binding must be just right
What happens with weak binding?
Death by neglect
What happens with strong binding?
Apoptosis
What happens with intermediate binding?
Survival
What happens with slightly high affinity?
Treg formation
What is lineage commitment?
Becoming CD4 or CD8 T cell
What determines CD4 vs CD8?
Type of MHC recognized
What is negative selection?
Removal of self-reactive T cells
What is self-tolerance?
Immune system ignores self
What are mechanisms of negative selection?
Apoptosis, anergy, Treg formation
What is AIRE?
Protein that presents self-antigens in thymus
What is positive selection characterized by?
Cortex location, self-MHC recognition, ~5% survival
What is negative selection characterized by?
Medulla location, removal of self-reactive cells